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Published on: March 24, 2017
Peroxisome proliferator-activated receptor gamma interacts with CIITA x RFX5 complex to repress type I collagen gene
Yong Xu1, Stephen R Farmer, Barbara D Smith
1Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Abstract:
Recent reports demonstrate that peroxisome proliferator-activated receptor gamma (PPARgamma), a member of the nuclear receptor superfamily, acts as a repressor of type I collagen synthesis. Our data demonstrate that exogenously expressed PPARgamma down-regulates collagen expression in a dose-responsive manner in human lung fibroblast cells. Silencing PPARgamma using lentiviruses expressing short hairpin RNAs partially reverses interferon-gamma (IFN-gamma)-induced repression and activates collagen mRNA levels. Previous studies indicate that IFN-gamma represses collagen gene expression and induces major histocompatibility complex II (MHC II) expression by activating the formation of a regulatory factor for X-box 5 (RFX5) complex with class II transactivator (CIITA). This report demonstrates that PPARgamma is within the RFX5.CIITA complex as judged by co-immunoprecipitation and DNA affinity precipitation studies. Most importantly, occupancy of PPARgamma on the collagen transcription start site and MHC II promoter increases with IFN-gamma treatment. The PPARgamma agonist, troglitazone, sensitizes the cells to IFN-gamma treatment by increasing recruitment of PPARgamma to collagen gene while repressing collagen expression, and these effects are blocked by the PPARgamma antagonist T0070907. PPARgamma may mediate IFN-gamma-stimulated collagen transcription down-regulation and MHC II up-regulation by interacting with CIITA as well as regulating CIITA expression. Therefore, PPARgamma is a critical target for investigations into therapeutics of diseases involving extracellular matrix remodeling and the immune response.
Insights
Peroxisome proliferator-activated receptor gamma (PPARgamma) represses collagen synthesis. PPARgamma interacts with CIITA to regulate collagen and MHC II expression, offering therapeutic targets for matrix remodeling and immune response diseases.
Area of Science:
- Molecular Biology
- Immunology
- Cell Biology
Background:
- Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor superfamily member.
- PPARgamma has been reported to repress type I collagen synthesis.
- Interferon-gamma (IFN-gamma) represses collagen gene expression and induces major histocompatibility complex II (MHC II) expression.
Purpose of the Study:
- To investigate the role of PPARgamma in collagen synthesis regulation.
- To determine the mechanism by which IFN-gamma represses collagen expression.
- To explore PPARgamma as a potential therapeutic target.
Main Methods:
- Exogenous expression and silencing of PPARgamma in human lung fibroblast cells.
- Co-immunoprecipitation and DNA affinity precipitation assays.
- Treatment with PPARgamma agonist (troglitazone) and antagonist (T0070907).
Main Results:
- Exogenous PPARgamma down-regulates collagen expression in a dose-dependent manner.
- Silencing PPARgamma reverses IFN-gamma-induced collagen repression.
- PPARgamma is part of the RFX5.CIITA complex and its occupancy increases with IFN-gamma treatment.
- PPARgamma agonist enhances IFN-gamma effects, while antagonist blocks them.
Conclusions:
- PPARgamma mediates IFN-gamma-induced collagen transcription down-regulation and MHC II up-regulation.
- PPARgamma interacts with CIITA to regulate collagen and MHC II expression.
- PPARgamma is a critical target for diseases involving extracellular matrix remodeling and immune response.
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